Identification of a potent heterocyclic ligand to somatostatin receptor subtype 5 by the synthesis and screening of β-turn mimetic libraries

Methods for the parallel synthesis of medium-ring heterocyclic beta-turn mimetics (1) are described, which enable the rapid preparation of libraries of mimetics for the identification of small molecule ligands to receptors. The generality of this method was first demonstrated by the rapid and high-yielding synthesis of mimetics la-g that display a wide range of proteinogenic amino acid side chains. Small molecule heterocyclic mimetics of the medicinally important peptide somatostatin were then identified by the synthesis of a focused library of beta-turn mimetics based upon the crucial Trp-Lys motif found in the turn region of somatostatin. Screening the library against a panel of the five cloned human somatostatin receptors (hSST(1)-hSST(5)) resulted in the identification of a potent small molecule ligand (Ih) with selectivity toward hSST(5), as well as potent ligands toward receptor subtypes 1-4, Furthermore, structure-activity relationships were used to establish the importance of each of the three diversity inputs present in compound Ih. This investigation represents the first successful identification of potent, small molecule ligands through the synthesis and evaluation of a focused library of turn mimetics (for one example of a successful screening effort of a nonfocused beta-turn library, see: Souers, A. J.; Virgilio, A. A.; Schurer, S.; Ellman, J. A.; Kogan, T. P.; West, H. E.; Ankener, W.; Vanderslice, P. Bioorg. Med. Chem. Lett. 1998, 8, 2297-2302). The results of the library screening revealed unexpected stereochemical and functional group preferences, reinforcing the critical importance of synthesizing and evaluating collections of mimetics as opposed to traditional iterative synthesis and evaluation approaches. The ability to prepare libraries of heterocyclic turn mimetics that display three different side-chain inputs with multiple distinct side-chain orientations should enable the rapid identification of small molecule heterocyclic ligands to a large number of receptor targets.